PROJECT SUMMARY/ABSTRACT This career development proposal is designed to provide the Principal Investigator, Dr. Lavannya M. Pandit, with the necessary knowledge, skills, and experience required for her transition to an independent translational researcher in the field of pulmonary hypertension. Dr. Pandit is a well-trained pulmonary specialist who has cared for veterans with pulmonary hypertension due to advanced lung disease for the last eight years. She brings a strong research background to this project including unique skills in obtaining and handling human lung tissue. Dr. Pandit outlines a four-year plan to investigate the basic mechanism by which a novel potassium channel, TWIK-2, regulates pulmonary arterial tone, and specifically how it participates in pulmonary vasoconstriction, a defining characteristic of pulmonary hypertension. This work will be performed under the mentorship of Dr. Rolando Rumbaut, Associate Professor of Medicine, and Section Chief of the Pulmonary/Critical Care/Sleep Medicine section at the Michael E. DeBakey VA Medical Center (MEDVAMC). The co-mentor on this proposal is Dr. Robert M. Bryan, Professor of Anesthesiology and Director of Cerebrovascular Research at Baylor College of Medicine, the affiliated academic institution of the DeBakey VAMC. Both mentors have collaborated with each other as vascular physiologists and have the funding and track record of mentoring young investigators for successful careers in academic medicine. Dr. Pandit also has the support of a team of exceptional collaborators at MEDVAMC, Baylor College of Medicine, and the Methodist Hospital. In addition, Dr. Pandit will acquire training through didactic coursework in cardiovascular physiology within the structure of the Baylor College Of Medicine Clinical Scientist Training Program. Dr. Pandit's past academic experiences underscore her commitment to academic medicine and her desire to pursue translational research in pulmonary hypertension. Having completed an NIH research training grant, since 2011, her research has evolved to focus on the role of potassium channels in the regulation of pulmonary vascular tone in an effort to meld her research with her clinical expertise in pulmonary hypertension. She now requires training in pulmonary physiology in both human and murine models of disease during this mentored period of scientific investigation. The research in this proposal will focus on the role of TWIK-2 in the development of pulmonary hypertension. The scientific approach will involve the utilization of pulmonary vessels of mice in which the TWIK-2 gene has been genetically knocked out as well as freshly explanted native human pulmonary vessels from patients with and without pulmonary hypertension, obtained at lung transplantation. Specific Aims of the project are to delineate how TWIK-2 affects the electrical properties of pulmonary smooth muscle cells, intracellular calcium levels, and the contractile properties of pulmonary vessels. The scientific training obtained through this grant will lead to publications and experience that will enable the candidate to secure independent funding within the next four years and establish herself an a translational investigator in pulmonary hypertension.